4.7 Article

Up-regulation of nPKC contributes to proliferation of mice pulmonary artery smooth muscle cells in hypoxia-induced pulmonary hypertension

Journal

EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 900, Issue -, Pages -

Publisher

ELSEVIER
DOI: 10.1016/j.ejphar.2021.174046

Keywords

Novel protein kinase C; Protein kinase C; Hypoxia; Pulmonary hypertension; Pulmonary artery smooth muscle cells; Proliferation

Funding

  1. Youth Program of National Natural Science Foundation of China [81803282]
  2. Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi [2020L0193]
  3. Doctoral Start-up Fund of Shanxi Medical University [03201520]
  4. Shanxi Province Foundation for Returnees [2020-087, 2020-086, 2020-167]

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This study investigated the role of nPKC in mediating PASMCs proliferation in PH. The findings revealed that hypoxia promoted PASMCs proliferation, with the most significant effect observed after 72 hours of treatment. The upregulation of PKC8 and PKC? expression under hypoxia led to PASMCs proliferation via the upregulation of AKT and ERK phosphorylation. These results suggest potential novel targets for molecular therapy of pulmonary hypertension.
This study is designed to investigate the role of novel protein kinases C (nPKC) in mediating pulmonary artery smooth muscle cells (PASMCs) proliferation in pulmonary hypertension (PH) and the underlying mechanisms. Mouse PASMCs was isolated using magnetic separation technology. The PASMCs were divided into 24 h group, 48 h group and 72 h group according to different hypoxia treatment time, then detected cell proliferation rate and nPKC expression level in each group. We treated PASMCs with agonists or inhibitors of PKCdelta (PKC8) and PKCepsilon (PKC?) and exposed them to hypoxia or normoxia for 72 h, then measured the proliferation of PASMCs. We also constructed a lentiviral vector containing siRNA fragments for inhibiting PKC8 and PKC? to transfected PASMCs, then examined their proliferation. PASMCs isolated successfully by magnetic separation method and were in good condition. Hypoxia promoted the proliferation of PASMCs, and the treatment for 72 h had the most significant effect. Hypoxia upregulated the expression of PKC8 and PKC? in mouse PASMCs, leading to PASMCs proliferation. Moreover, Our study demonstrated that hypoxia induced upregulation of PKC8 and PKC? expression resulting to the proliferation of PASMCs via up-regulating the phosphorylation of AKT and ERK. Our study provides clear evidence that increased nPKC expression contributes to PASMCs proliferation and uncovers the correlation between AKT and ERK pathways and nPKC-mediated proliferation of PASMCs. These findings may provide novel targets for molecular therapy of pulmonary hypertension.

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